Systems Toxicology of Bisphenol A: Mechanistic Overlap in Metabolic and Reproductive Disruption.

Bisphenol-A: A Powerful Endocrine Disrupting Chemical

Edaravone counteracts redox and metabolic disruptions in an emerging zebrafish model of sporadic ALS

Probing the bioconcentration and metabolism disruption of bisphenol A and its analogues in adult female zebrafish from integrated AutoQSAR and metabolomics studies

SWATH-MS reveals that bisphenol A and its analogs regulate pathways leading to disruption in insulin signaling and fatty acid metabolism

Binding and activity of bisphenol analogues to human peroxisome proliferator-activated receptor β/δ

Bisphenol S toxicity in zebrafish: Endocrine, neurobehavioural, and metabolic disruptions.

Serum unconjugated bisphenol A concentrations in women may adversely influence oocyte quality during in vitro fertilization

Inappropriate programming of the reproductive system by developmental exposure to excess steroid hormones is of concern. Sheep are well suited for investigating developmental origin of reproductive and metabolic disorders. The developmental time line of female sheep (approximately 5 mo gestation and approximately 7 mo to puberty) is ideal for conducting sequential studies of the progression of metabolic and/or reproductive disruption from the developmental insult to manifestation of adult consequences. Major benefits of using sheep include knowledge of established critical periods to target adult defects, a rich understanding of reproductive neuroendocrine regulation, availability of noninvasive approaches to monitor follicular dynamics, established surgical approaches to obtain hypophyseal portal blood for measurement of hypothalamic hormones, and the ability to perform studies in natural setting thereby keeping behavioral interactions intact. Of importance is the ability to chronically instrument fetus and mother for determining early endocrine perturbations. Prenatal exposure of the female to excess testosterone (T) leads to an array of adult reproductive disorders that include LH excess, functional hyperandrogenism, neuroendocrine defects, multifollicular ovarian morphology, and corpus luteum dysfunction culminating in early reproductive failure. At the neuroendocrine level, all 3 feedback systems are compromised. At the pituitary level, gonadotrope (LH secretion) sensitivity to GnRH is increased. Multifollicular ovarian morphology stems from persistence of follicles as well as enhanced follicular recruitment. These defects culminate in progressive loss of cyclicity and reduced fecundity. Prenatal T excess also leads to fetal growth retardation, an early marker of adult reproductive and metabolic diseases, insulin resistance, hypertension, and behavioral deficits. Collectively, the reproductive and metabolic deficits of prenatal T-treated sheep provide proof of concept for the developmental origin of fertility and metabolic disorders. Studies with the environmental endocrine disruptor bisphenol A (BPA) show that reproductive disruptions found in prenatal BPA-treated sheep are similar to those seen in prenatal T-treated sheep. The ubiquitous exposure to endocrine disrupting compounds with steroidogenic potential via the environment and food sources calls for studies addressing the impact of developmental exposure to environmental steroid mimics on reproductive function.

Bisphenol A (BPA) is a synthetic organic compound commonly utilized in the manufacturing of polycarbonate plastics and epoxy resins. Its widespread presence in everyday items, including water bottles, food containers, and thermal paper, has raised considerable health concerns due to its potential as an endocrine disruptor. BPA has the ability to mimic estrogen and bind to estrogen receptors, which can lead to disruptions in hormonal signaling pathways. This interference poses risks to reproductive health, especially among younger individuals, as it may result in irregular menstrual cycles, ovulation issues, and compromised spermatogenesis. Research indicates that BPA exposure can adversely affect ovarian function, diminish sperm quality, and induce oxidative stress and inflammation, further compromising fertility. The potential for BPA to cause long-term health effects through epigenetic modifications, alongside its prevalence in food contact materials, underscores the urgent need for strategies to minimize exposure. Recommended approaches include the use of BPA-free products, choosing fresh foods over canned items, and advocating for stricter regulations. A deeper understanding of the mechanisms underlying BPA’s reproductive toxicity is essential for developing effective interventions. Additionally, research is needed to address critical gaps in knowledge regarding the cumulative effects of low-dose exposure, transgenerational impacts, and the specific effects on male fertility. Investigating epigenetic mechanisms, variability in susceptibility, and the safety of BPA alternatives is paramount. Furthermore, exploring effective interventions, increasing public awareness, and implementing regulatory measures are crucial steps in mitigating BPA’s adverse effects on reproductive health.

Proceedings of the Summit on Environmental Challenges to Reproductive Health and Fertility: executive summary

Proceedings of the Summit on Environmental Challenges to Reproductive Health and Fertility: executive summary

Environmental Health Perspectives (EHP) established the Paper of the Year in 2008 (Tilson 2008) as a way of highlighting high-quality articles published in the journal. The EHP Classic Paper of the Year is given to the most highly cited Research Article, Commentary, or Review Article over the preceding 60 months. We are proud to announce that the 2012 EHP Classic Paper of the Year is “Exposure of the U.S. Population to Bisphenol A and 4-tertiary-Octylphenol: 2003–2004” by Antonia M. Calafat, Xiaoyun Ye, Lee-Yang Wong, John A. Reidy, and the late Larry L. Needham of the Division of Laboratory Sciences, National Center for Environmental Health, Centers for Disease Control and Prevention. This article (Calafat et al. 2008) was published in the January 2008 issue of EHP; since its publication it has been cited > 40 times/year. When the paper was published, public and scientific concerns related to health and exposure to bisphenol A (BPA) had already emerged. BPA, a high production volume chemical, is used worldwide to manufacture many consumer items, such as reusable water bottles and food containers; linings of metal food cans; medical devices and impact-resistant safety equipment; and polyvinyl chloride, paper, and cardboard products. Results from animal studies suggested that exposures to BPA can lead to developmental, reproductive, and other adverse health effects. Yet, important knowledge gaps remained regarding the relevance of these findings to human health, in part, because of limited information on human exposure to BPA. Calafat et al. (2008) addressed this gap using bio-monitoring—the accurate and precise measurement of trace levels of environ-mental chemicals in a person’s body—to investigate the degree of the U.S. general population’s exposures to BPA. Calafat et al. (2008) used state-of-the-art analytical chemistry methods to measure the urinary levels of BPA in a representative sample of the U.S. population: 2,517 participants > 6 years of age in the 2003–2004 National Health and Nutrition Examination Survey (NHANES). The study demonstrated that almost 93% of the NHANES participants were exposed to BPA. Because BPA is transformed and eliminated from the body within a few hours after exposure, the high percentage of people with detectable BPA suggested frequent or almost continuous exposure of the U.S. general population to this chemical. Furthermore, using urinary levels of BPA to categorize exposures, Calafat et al. (2008) showed that exposure differed by race/ethnicity, age, sex, and household income, suggesting that exposure may be influenced by multiple factors. The authors’ findings on BPA exposure also highlighted the need for additional public health research. Calafat et al. established the framework that led the way for future studies to identify sources and routes of exposure to BPA and to evaluate potential health effects resulting from such exposures. Since the publication of the paper, our knowledge of exposure to BPA has greatly improved. For example, in addition to diet (still believed to be the main contributor to exposure for the general population), we now know that medical interventions (e.g., Calafat et al. 2009) and thermal paper products such as store receipts (e.g., Biedermann et al. 2010) can also contribute to BPA exposure. Moreover, additional high-quality biomonitoring studies of populations exposed to BPA—published since the Calafat et al. (2008) paper—have increased our understanding of the potential links between BPA exposures and human health. This exposure information will be useful for risk assessment (e.g., to set intervention and research priorities and evaluate the effectiveness of public health measures), as well as to monitor exposure trends. EHP congratulates Calafat and colleagues for their contribution to the environmental health science literature. Their work clearly illustrates the utility of human biomonitoring to estimate population-based exposures. These exposure and health effects studies will ultimately inform policy decisions regarding human exposure levels and direct appropriate public health actions.

Study question Does a pre- and postnatal exposure to two widespread EDCs, bisphenol A (BPA) and benzophenone-3 (BP-3), affect offspring gonadal function in mice? Summary answer Combined pre- and postnatal exposure to BPA and BP-3 affects gonadal function in mice with possible long-term implications for fertility in both sexes. What is known already Endocrine disrupting chemicals (EDCs) are found ubiquitously in the environment and are used in many products of everyday life. Exposure to EDCs at environmental concentrations can pose significant risks to male and female health and fertility. EDCs have estrogen-like, antiestrogenic or antiandrogenic properties that can affect reproductive and immune function in multiple ways. Especially during sensitive developmental periods and at reproductive age, continuous exposure to EDCs and EDC-mixtures poses long-term risks for reproductive health. Given that the number of medically assisted reproduction patients is increasing in many countries, there is need to understand the effects of EDCs to reproductive health. Study design, size, duration We exposed pregnant mice from gestation day 0 to postnatal day (P) 21 to BPA (oral), BP-3 (dermal), both BPA and BP-3, or control substances (10 animals/group) at concentrations relevant for environmental exposure. Ten female offspring/group underwent superovulation by pregnant-mare serum gonadotropin and human chorionic gonadotropin (hCG) treatment at P28 and P30, respectively. Females were dissected 13 h after hCG-treatment, males (10 per group) were sacrificed on P56 and P100 to retrieve tissues for analysis. Participants/materials, setting, methods After dissection, ovaries were embedded in paraffin, sectioned and stained with hematoxylin/eosin to count healthy and atretic follicles and measure corpus luteum development. Flow cytometry was used to determine immune cells in the ovaries and gene expression of different ovarian markers was analyzed by qPCR. Ovulated oocytes were counted in hCG-treated females by microscopy. Male offspring testes were dissected to determine epididymal sperm count by light-microscopy and gene expression of testicular markers by qPCR. Main results and the role of chance In female offspring, we observed significantly fewer secondary follicles following BPA, BP-3 and BPA+BP-3 exposure (P < 0.05), and an increase in atretic follicles (P < 0.05) when exposed to BP-3 and BPA+BP-3 compared to controls. BPA+BP-3 exposure also caused an increase in ovarian NK cell number (P < 0.05), and altered ovarian estrogen receptor 1 and 2 (P < 0.05 and < 0.0001), androgen receptor (P < 0.05), and hormone-metabolizing enzyme Cyp11a1 (P < 0.05) gene expression. Ovarian response to exogenous gonadotropins (PMSG and hCG) was impaired leading to significantly fewer oocyte-cumulus-complexes in BPA (P < 0.05) and BPA+BP-3 (P < 0.05) exposed females. In male offspring on P56, total sperm count was altered (P < 0.05) and gene expression of androgen-metabolizing enzymes Cyp11a1 (P < 0.01), Cyp17a1 and Cyp19a1 (P < 0.05) in the testis was significantly decreased following BPA+BP-3 exposure compared to controls. On P100, these differences in sperm count and gene expression were no longer observed between BPA-BP-3 exposed offspring and controls. Limitations, reasons for caution Our study provides insights into effects of EDCs for male and female reproduction in a model organism that need verification in human epidemiology and in vitro studies. Further studies are needed to determine the long-term consequences for reproduction and underlying mechanisms in mice and humans. Wider implications of the findings The results suggest that low, environmentally relevant concentrations of widespread EDCs significantly affect male and female reproductive organs following pre- and postnatal exposure. Especially EDC mixtures have not been studied in great detail and may be a significant risk for reproductive health. Trial registration number No

Riverine populations that rely on contaminated water bodies for everyday activities and food sources are most affected by the growing environmental and public health concern of microplastic pollution in river ecosystems. One of the world's most polluted rivers, the Citarum River is a high-risk environment for long-term exposure to microplastics, which may have an impact on women's reproductive health. An analytical cross-sectional design with an environmental and biomonitoring approach was applied to women of reproductive age (18–45 years) who had resided in the study area for at least two years, representing chronic exposure conditions. Environmental samples of river water, sediment, and locally consumed fish were analyzed using micro-FTIR or Raman spectroscopy, with polymer confirmation by Py-GC-MS. Individual exposure was assessed through fecal microplastic counts and urinary measurement of plastic-related chemical biomarkers, including phthalate metabolites (MEHP) and bisphenol A (BPA). The results demonstrated elevated levels of microplastics in environmental matrices and biological samples. Higher exposure categories were consistently associated with increased oxidative stress and inflammatory biomarkers, reduced anti-Müllerian hormone levels, elevated gonadotropins, and a higher prevalence of menstrual cycle disturbances. These findings indicate a dose–response pattern linking chronic microplastic exposure with biological stress and reproductive dysfunction. Overall, this study provides empirical evidence that long-term exposure to microplastics in contaminated river environments may pose a significant risk to women’s reproductive health, underscoring the need for environmental control and targeted public health interventions.

Exposure of zebrafish larvae to bisphenol A, bisphenol S, di-(2-ethylhexyl) phthalate, and di-(2-ethylhexyl) adipate induces oxidative stress, resulting in hepatotoxicity and disruption in lipid metabolism.